Cell Biology (Cytoskeleton and Cell Cycle)

1976

M.D. Faculty of Medicine, Mie University

1982

Ph.D. Faculty of Medicine, Mie University

1986

Researcher, Laboratory of Experimental Radiology,
Aichi Cancer Center Research Institute

1991

Senior Researcher, Laboratory of Experimental Radiology,
Aichi Cancer Center Research Institute

1992

Head (Chief), Department of Neurophysiology,
Tokyo Metropolitan Institute of Gerontology

1996-present

Chief, Division of Biochemistry,
Aichi Cancer Center Research Institute

2007-present

Visiting Professor, Department of Cellular Oncology,
Graduate School of Medicine, Nagoya University,

The study on the mechanism of functional molecules in tumor cells

We found that vimentin, an intermediate filament (IF) protein, is disassembled through phosphorylation by protein kinase A (Nature, 1987). Earlier reports established a theory that IF has stable and insoluble structures. However, our observation overturned a previous theory, and in turn showed a novel theory that IF is dynamically regulated by protein kinases. In 1990, we first established a method and procedures to develop site- and phosphorylation state-specific antibodies. By using those antibodies, we found that IF is cooperatively phosphorylated by Rho-kinase and Aurora-B during cytokinesis (J. Biol. Chem., 1998); Aurora-B phosphorylates at Ser28 on histone H3 during mitosis (J. Biol. Chem.,1999); Autophosphorylation of Aurora-B at Thr232 is an essential event for its activation (J. Biol. Chem., 2004); Vimentin phosphorylation by Cdk1 induces Plk1-meditaed vimentin phosphorylation during mitosis (J. Cell Biol., 2005); and Complex formation of INCENP phosphorylated by Cdk1 with Plk1 is required for metaphase-anaphase transition (Nat. Cell Biol., 2006). Furthermore, we observed that Chk1 phosphorylation by Cdk1 induces cytoplasmic translocation of Chk1 during mitosis, and plays a crtical role for mitotic onset. Thus, our produced a site- and phosphorylation state-antibody brought about rapid development in various research field, including signal transduction , cell cycle and cancer. Our research goal is to elucidate molecular mechanisms of carcinogenesis through investigations of regulation of cell cycle and cytoskeleton. For this purpose, our attention has been focused on the following areas: (1) Analysis of cell cycle regulation through protein phosphorylation by mitotic and checkpoint kinases; (2) Identification and characterization of novel intermediate filament-binding proteins to elucidate the mechanism of the regulation of cell adhesion machinery, including hemidesmosome and desmosome functions; and (3) Establishment of new system to visualize phosphorylated proteins in living cells.

Click to zoom

Click to zoom

1. Sugimoto M et al. The keratin-binding protein Albatross regulates polarization of epithelial cells. J. Cell Biol. in press (2008)
2. Li ZF et al. Non-pathogenic protein aggregates in skeletal muscle in MLF1 transgenic mice. J. Neurol. Sci. 264: 77-86 (2008)
3. Toyo-oka K et al. Protein phosphatase 4 catalytic subunit regulates Cdk1 activity and microtubule organization via NDEL1 dephosphorylation. J. Cell Biol. 180: 1133-1147 (2008)
4. Izawa I et al. Palmitoylation of ERBIN is required for its plasma membrane localization. Genes Cells 13: 691-701 (2008)
5. Lin YM et al. eIF3k regulates apoptosis in epithelial cells by releasing caspase 3 from keratin-containing inclusions. J. Cell Sci. 121: 2382-2393 (2008)
6. Goto H et al. Production of a site- and phosphorylation state-specific antibody. Nature Protocols 2: 2574-2581 (2007)
7. Goto H et al. Complex formation of Plk1 and INCENP required for Metaphase-anaphase transition. Nature Cell Biol. 8: 180-187 (2006)
8. Yamaguchi T et al. Phosphorylation by Cdk1 induces Plk1-mediated vimentin phosphorylation during mitosis. J. Cell Biol. 171: 431-436 (2005)
9. Ivaska J et al. PKCepsilon-mediated phosphorylation of vimentin controls integrin recycling and motility. EMBO J. 24: 3834-3845 (2005)
10. Minoshima Y et al. Aurora B Phosphorylates MgcRacGAP and Induces PhoGAP Activity during M Phase : Identification of a RhoGAP Indispensable for Cytokinesis. Dev. Cell 4: 549-560 (2003)
11. Inada H et al. Keratin attenuates tumor necrosis factor-induced cytotoxicity through association with TRADD. J. Cell Biol. 155: 415-425 (2001)
12. Hirota T et al. Zyxin, a regulator of actin filament assembly, targets the mitotic apparatus by interacting with h-warts/LATS1 tumor suppressor. J Cell Biol. 149: 1073-1086 (2000)
13. Kawano Y et al. Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase by Rho-kinase in vivo. J. Cell Biol. 147: 1023-1038 (1999)
14. Yasui Y et al. Roles of Rho-associated kinase in cytokinesis; Mutations in Rho-associated kinase phosphorylation sites impair cytokinetic segregation of glial filaments. J. Cell Biol. 143: 1249-1258 (1998)
15. Sekimata M et al. Detection of protein kinase activity specifically activated at metaphase-anaphase transition. J. Cell Biol. 132: 635-641 (1996)
16. Ogawara M et al. Differential targeting of protein kinase C and CaM kinase II signalings to vimentin J. Cell Biol. 131: 1055-1066 (1995)
17. Matsuoka Y et al. Two different protein kinases act on a different time schedule as glial filament kinase during mitosis. EMBO J. 11: 2895-2902 (1992)
18. Fukami K et al. Requirement of phosphatidylinositol 4.5-bisphosphate for α-actinin function. Nature 359: 150-152 (1992)
19. Nishizawa K et al. Specific localization of phospho-intermediate filament protein in the constricted area of dividing cells. J. Biol. Chem. 266: 3074-3079 (1991)
20. Okamoto T et al. Identification of Gs activator region of the β2-adrenergic receptor that is autoregulated via PKA-dependent phosphorylation. Cell 67: 723-730 (1991)
21. Ohno S et al.Tissue-specific expression of three distinct types of rabbit protein kinase C. Nature 325: 161-166 (1987)
22. Inagaki M et al. Site-specific phosphorylation induces disassembly of vimentin filaments in vitro. Nature 328: 649-652 (1987)

1987: Award of San-ikai; Biopharmacological study of protein kinase C
1994: Incitement Award of the Japanese Cancer Association; Biological significance of protein phosphorylation on the cytoskeleton disruption in malignant cells
2001: Award of Inoue Foundation for Science; Establishment of a site- and phosphorylation state-specific antibody, and its applicative study.